Pancreatic cancer is the fourth most frequent cause of cancer-related death in the U.S., and only about 5% of patients diagnosed with this disease survive. Pursuant to the goal of developing new treatments for pancreatic cancer, we propose to expand our studies on beta-secretase inhibitors and amyloid precursor-like protein 2 (APLP2). APLP2 is a member of a family of proteins that also includes amyloid precursor protein (APP). Our preliminary data show that APLP2 is amply expressed in pancreatic cancer cell lines and human pancreatic cancer tissues. APLP2 is found in transmembrane form at the cell surface, and its cleavage by beta-secretases leads to the release of C-terminal fragments from a secreted N-terminal domain. Beta-secretases, also called -site amyloid precursor protein cleaving enzyme 1 and 2 (BACE1 and BACE2), are transmembrane aspartic proteases. Inhibitors of beta-secretases are in development for the treatment of Alzheimer's disease by several companies, because in addition to cleaving APLP2 the beta-secretases also cleave APP, which is a step in the production of beta-amyloid (implicated in the etiology of Alzheimer's disease). Such inhibitors have a relatively good safety profile in mice and humans. In our preliminary studies, we have found that treatment with novel beta-secretase inhibitors reduces pancreatic cancer cell survival. Furthermore, we have shown that beta-secretase cleavage of amyloid precursor-like protein 2 (APLP2) is increased in transformed pancreatic ductal cells, and that inhibition of beta secretase cleavage of APLP2 correlates with reduced pancreatic cancer cell survival. The central hypothesis that we will test is that beta-secretase inhibitors block the cleavage of amyloid precursor-like protein 2 (APLP2), and thereby reduce the ability of pancreatic cancer cells to survive. Accomplishment of this project will elucidate the mechanism underlying the ability of beta- secretase inhibitors to decrease pancreatic cancer cell growth, and define the importance of APLP2 to the mechanism. The results from this study are anticipated to support future translational and clinical studies of beta-secretase inhibitors as novel therapies for pancreatic cancer. Furthermore, in addition to their translational potential, these studies are expected to provide new perspectives on the basic molecular regulation of pancreatic cancer cell survival.